Autoimmune disease refers to any of a group of disorders or diseases in which tissue injury is associated with a humoral and/or cell-mediated immune response to body constituents or, in a broader sense, an immune response “to self”. The pathological immune response may be systemic or organ specific. That is, for example, the immune response directed to self may affect joints, skin, the myelin sheath that protects neurons, kidney, liver, pancreas, thyroid, adrenals and ovaries. In fact, the list of autoimmune diseases is composed of more than eighty disorders. A few autoimmune diseases such as vitiligo, in which patches of skin lose pigmentation, are merely annoying. Most others are debilitating, often progressive with time and eventually fatal. Systemic lupus erythematosus (SLE), for example, is a chronic disease in which 10-15% of patients die within a decade of diagnosis. In all but a few autoimmune diseases, the sex ratio skews towards women. For example, in SLE the ratio of female to male patients is nine to one. In one particular case, Hashimoto's disease in which the immune system attacks the thyroid gland, the ratio is fifty to one.
It has long been known that immune complex formation plays a role in the etiology and progression of autoimmune disease. For example, in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 16th Edition (1980), Macmillan Publishing Co., on page 683, inflammation in patients with arthritis is stated to probably involve phagocytosis by leukocytes of complexes of antigen, antibody and complement—immune complexes. But it is only now being recognized that inflammation caused by immune complexes in the joints (arthritis), the kidneys (glomerulonephritis) and blood vessels (vasculitis) is a major cause of morbidity in autoimmune diseases as noted by P. M. Hogarth et al., Annual Reports in Medicinal Chemistry, 37, 217-224 (2002). Increased immune complex formation correlates with the presence of antibodies directed to self or so-called autoantibodies, and the presence of the latter can also contribute to tissue inflammation either as part of an immune complex or unbound to antigen (free antibody). In some autoimmune diseases, the presence of free autoantibody contributes significantly to disease pathology. This has been clearly demonstrated for example, in SLE (anti-DNA antibodies), ITP (antibody response directed to platelets) and to a lesser extent rheumatoid arthritis (IgG reactive rheumatoid factor). The importance of the role of immune complexes and free autoantibodies is further demonstrated by the fact that successful treatment of certain autoimmune diseases has been achieved by the removal of immune complexes and free antibody by specific immunoadsorption procedures. For example, the use of an apheresis procedure in which immune complexes and antibodies are removed by passage of a patient's blood through an immunoaffinity (Prosorba®) column was approved by the U.S. FDA in 1987 ITP and in 1999 for rheumatoid arthritis. Currently, however, there is no approved method for the treatment of autoimmune diseases which facilitates the elimination of immune complexes and autoantibodies by administration of a drug.
Another aspect of the etiology and progression of autoimmune disease is the role of proinflammatory cytokines. Under normal circumstances, proinflammatory cytokines such as tumor necrosis factor α (TNFα) and interleukin-1 (IL-1) play a protective role in the response to infection and cellular stress. But the pathological consequences which result from chronic and/or excessive production of TNFα and IL-1 are believed to underlie the progression of many autoimmune diseases such as rheumatoid arthritis, Crohn's disease, inflammatory bowel disease and psoriasis. Other proinflammatory cytokines include interleukin-6, interleukin-8, interleukin-17 and granulocyte-macrophage colony stimulating factor. It appears, however, that TNFα is on the top of the proinflammatory cytokine cascade. That is, in terms of blocking one proinflammatory cytokine, blockage of TNFα would provide the maximum therapeutic effect. The ability of TNFα to downregulate other proinflammatory cytokines is reviewed by M. Feldmann in Perspectives, 2:364-371 (2002). Indeed, the impact of the antagonism of TNFα as a treatment option for arthritis, psoriatic arthritis, psoriasis and Crohn's disease has been illustrated by the U.S. FDA approval of Remicade (chimeric anti-TNFα monoclonal antibody), Enbrel (soluble TNFα p75 receptor fusion protein) and Humira (human anti-TNFα monoclonal antibody).
As may be inferred from the above discussion regarding the etiology and progression of autoimmune disease, its pathogenesis is complex and multifactorial. As such, there arm a multitude of therapies available. But the majority of autoimmune diseases are poorly controlled by current treatments. Conventional treatments are not uniformly effective and are often associated with moderate to severe toxicity. Nonetheless, the above discussion indicates that there is a need for simple, well-defined organic compounds which can help the body eliminate immune complexes or at least prevent the deposition of circulating immune complexes and/or (simultaneously) inhibit the activity of TNFα while still being generally nontoxic to the patient. In summary, there is a need for an efficacious yet nontoxic treatment of chronic autoimmune disease.
The present invention provides compounds that are useful for the treatment of chronic autoimmune disease. Although not initially life-threatening, most autoimmune diseases are chronic conditions which slowly progress to a debilitating state. While numerous therapies are available, conventional treatments are not routinely efficacious. More problematic is the accompanying toxicity which often prohibits the long-term use necessary with a chronic disease. Current treatments for autoimmune disease can be broadly classified into two groups: those drugs which dampen or suppress the immune response to self and those drugs which address the symptoms that arise from chronic inflammation. In greater detail, conventional treatments for autoimmune disease (e.g., primarily arthritis) are as follows:    1. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): These include aspirin, ibuprofen, naproxen, etodolac and ketoprofen. NSAIDs are not relatively potent drugs and so are most commonly used as anti-inflammatory drugs in the early stages of disease (e.g., to relieve the pain and swelling which accompanies arthritis). But NSAIDs are associated with gastrointestinal irritation and liver toxicity. In order to address the gastrointestinal ulceration associated with the use of many NSAIDs, more selective NSAID drugs have been recently developed which selectively inhibit (Vioxx, Celebrex) or preferentially inhibit Mobicox) cyclooxygenase-2 (COX-2 inhibitors). COX-2 inhibitors, however, display untoward side effects which include gastrointestinal irritation, especially with longer-term use.    2. Corticosteroids: These include prednisone and dexamethasone. Corticosteroids are the most widely used anti-inflammatory agents for the treatment of rheumatoid arthritis. But they significantly increase the risk of osteoporosis, gastrointestinal toxicity and infection arising from generalized immune suppression. Therefore, corticosteroids tend to be used for the treatment of disease flares (e.g., SLE) and not as a chronic treatment.    3. Disease-Modifying Anti-Rheumatic Drugs (DMARDs): These include cytotoxic drugs such as methotrexate, azathioprine and cyclophosphamide, potent immunosuppressants such as cyclosporin A (Sandimmune, Neoral) and FK506 (tacrolimus) and a variety of other drugs such as hydrocloroquine and organogold salts (e.g., aurothioglucose). DMARDs are potent drugs and so can display significant efficacy in reducing inflammation and slowing the rate of disease progression. As such, physicians have traditionally used DMARDs as a second line of therapy after NSAIDs. As potent drugs, however, DMARDs have significant toxicity associated with their use. Cytotoxic drugs, for example, interfere with DNA replication which manifests itself with a number of toxic effects. The latter include bone marrow depression and subsequent risk of infection and neoplasia. The use of cyclosporin A and FK506 is limited by serious side effects which include renal and liver toxicities. Toxic effects associated with the use of hydrochloroquine include blindness, neuromyopathy and gastrointestinal distress. The most common side effect arising from therapy with gold salts is dermatitis. But gold toxicity can also cause nephritis and bone marrow depression.    4. Biologicals: These include the recombinant proteins Remicade, Enbrel and Humira, all of which target TNFα, Kineret, which targets interleukin-1, Amevive, which targets T-cells (CD2 surface glycoprotein) and Raptiva which also targets T-cells (anti-CD11a antibody). But recombinant proteins and, in particular, recombinant antibodies are difficult to produce for widespread use and have toxic side effects associated with their use. Toxicities include potential immunological reactions, especially with the prolonged use that may be required for chronic conditions. In addition to the well-known HAMA (human anti-mouse antibody) response associated with chimeric or human antibodies, antibody mediated cytotoxicity mechanisms (ADCC and complement-mediated) may lead to side effects. More recently, it was discovered that antibodies, regardless of source or antigen specificity, can convert molecular oxygen into hydrogen peroxide and ozone as described by P. Wentworth et al. Science 293, 1806-1811 (2001) and 298, 2195-2199 (2002). This could lead to cellular and tissue damage which may exacerbate treatment of an autoimmune condition with prolonged use. For example, it was shown that the production of hydrogen peroxide and ozone by antibodies could be linked to an inflammatory response in rats: a so-called Arthus reaction. The potent anti-TNFα activity of the antibody Remicade has led to increased risk of opportunistic infections which include tuberculosis, histoplasmosis, listeriosis and pneumocytosis.
Therefore, it is an objective of the present invention to provide novel compounds for use in treating autoimmune disease.